Imidazaolone derivatives,preparation thereof and biological use of same

ABSTRACT

Imidazolone derivatives, as medicaments, of formula 
     
       
         
         
             
             
         
       
     
     wherein:
         R 1 ═H, C 1  to C 5  alkyl, aryl or a 5- or 6-membered heterocyclic group;   Ar 1 =optionally substituted aryl or an aromatic heterocycle;   R═R 2 —S—, R 3 —HN—, R 4 COHN or Ar 2 , with
           R 2 =a C 1 -C 5  alkyl, vinyl or vinyl(C 1 -C 5 )alkyl, nitrile or nitrile(C 1 -C 5 )alkyl, aryl or benzyl radical, which are optionally substituted;   R 3 =the meanings given above and H;   Ar 2 =substituted or unsubstituted aryl.

The subject of the invention is imidazolone derivatives. The inventionalso relates to a method for the preparation thereof.

It also relates to the biological uses of these derivatives as kinaseinhibitors, in particular for the treatment of neurodegenerativediseases (especially Alzheimer's disease, Pick's disease and trisomy21).

The vast majority of human pathological conditions involvephosphorylation abnormalities, often associated with abnormalities inregulation of certain protein kinases.

The search for effective inhibitors of these kinases has thus been veryactive over the past few years.

Using their long experience concerning kinases, CDKs, GSK-3 and CK1 as abasis for support, the inventors have focused on the production ofinhibitors selective for the DYRK1A kinase (Dual-specificityTyrosine-phosphorylation-Regulated Kinase 1 A).

It is an enzyme which autophosphorylates on its Tyrosine 321 (therebyresulting in its activation) and which phosphorylates Serine andThreonine residues.

The DYRK1A protein kinase gene is located in a quite specific region ofchromosome 21, the “Down's syndrome critical region”, which covers about20 genes responsible for the trisomic phenotype. Many arguments supportthe hypothesis that even a modest (×1.5) overexpression of DYRK1A makesan essential contribution to the abnormal development of the brainobserved during trisomy 21. Moreover, DYRK1A also appears to be highlyinvolved in Alzheimer's disease (which appears in individuals sufferingfrom trisomy 21 systematically and early after the age of about 40)(Kimura R, et al., 2006. The DYRK1A gene, encoded in chromosome 21 Downsyndrome critical region, bridges between beta-amyloid production andtau phosphorylation in Alzheimer disease. Hum Mol Genet. 16, 15-23;Ferrer I, et al., 2005. Constitutive Dyrk1A is abnormally expressed inAlzheimer disease, Down syndrome, Pick disease, and related transgenicmodels. Neurobiol Dis. 20, 392-400).

DYRK1A inhibitors have been sought by virtual screening in silico on astructural model of DYRK1A based on the crystalline structure of GSK-3(Kim et al., Bioorg. Med. Chem. Lett., 2006 Jul. 15; 16 (14):3712-6). Inthis approach, out of the 182 compounds selected, only 11 moleculesshowed an inhibitory activity with an IC₅₀ ranging from 2.5 to 50 μM.

The studies by the inventors in order to search for, optimize andcharacterize pharmacological inhibitors of the DYRK1A kinase have ledthem to discover that imidazolone derivatives corresponding toderivatives or analogs of leucettamine B constitute, in this respect,potent and selective pharmacological inhibitors of the DYRK1A kinase.Hereinafter, the term “compounds” will also be used to denote thesederivatives and analogs as a whole.

Leucettamine B is a marine alkaloid extracted from the sponge Leucettamicroraphis, of formula A

Research development has led the inventors to set up synthesis pathwaysfor obtaining a family of compounds having inhibitory properties ofgreat interest with respect to DYRK1A, with IC₅₀ values of mostly lessthan 50 μM and even than 10 μM, or even 1 μM.

The invention therefore relates to the use, as medicaments, ofimidazolone derivatives constituting leucettamine B analogs andderivatives.

It also relates to a process for preparing these compounds.

The invention also relates to the compounds which correspond to novelimidazolone derivatives and to the uses thereof as active ingredients ofmedicaments.

According to a first aspect, the invention thus relates to the use, forproducing medicaments for the treatment of neurodegenerative diseases,of imidazolone derivatives corresponding to formula (I)

in which:

-   -   R₁ represents H, a linear or branched, optionally substituted,        C₁ to C₅ alkyl radical; an aryl group, or a 5- or 6-membered        heterocyclic group, the aryl group and the heterocyclic group        optionally comprising one or more substituents, which may be        identical or different, occupying any positions;    -   Ar₁ represents an aryl group with optionally one or more        substituents, it being possible for two adjacent substituents to        form a 5- or 6-membered ring, this ring being, where        appropriate, substituted; or an aromatic heterocycle with        optionally one or more substituents and/or condensed with a 5-        or 6-membered aromatic ring, the heteroatom being chosen from N,        S and O;    -   R represents R₂—S—, R₄COHN or Ar₂, with        -   R₂=a linear, branched or cyclic C₁-C₅ alkyl radical; a vinyl            or vinyl(C₁-C₅)alkyl radical, a nitrile or            nitrile(C₁-C₅)alkyl radical, or an aryl or benzyl radical,            said radicals being optionally substituted on one or more            carbon atoms with one or more groups, which may be identical            or different, occupying any positions, it being possible for            two adjacent substituents to form a 5- or 6-membered ring,            this ring being, where appropriate, substituted,        -   R₃=the meanings given above and may also represent H;        -   Ar₂ representing a substituted or unsubstituted aryl            radical, it being possible for two adjacent substituents to            form a 5 or 6-membered ring, this ring being optionally            substituted.

The invention also relates to the racemic forms of the above derivativesand also the enantiomeric forms thereof taken individually.

As illustrated by the examples, the above derivatives more especiallyconstitute selective inhibitors of the DYRK1A kinase with IC₅₀ values ofless than 5 μM, or even less than 1 μM, particularly advantageousderivatives having IC₅₀ values of less than 0.1 μM.

In formula (I) above, “aryl” represents phenyl or naphthyl and“heterocycle” represents a 5- or 6-membered ring with N, O and/or S asheteroatom(s). The substituents of R₁, Ar₁, Ar₂ and R are chosen from:OH, OZ, COH, COZ, COOH, COOZ, NH₂, NHalk., N(alk.)₂, NHCOOH, NHCOOZ, Zrepresenting a linear or branched C₁-C₅ alkyl, aryl, benzyl, substitutedbenzyl or aryl, or benzodioxolyl radical, one or more halogens and/or aCCl₃ group, and alk. representing a C₁-C₃ alkyl radical.

The invention relates more especially, for use as medicaments, toimidazalone derivatives having an IC₅₀ of less than 5 μM andcorresponding to formula I above in which:

-   -   R₁ represents a C₁-C₃ alkyl radical or a hydrogen atom, and/or        an aryl radical,    -   Ar₁ is chosen from

-   -   R represents        -   an R₂—S— group, R₂ then being chosen from radicals of            T₁-(CH₂)_(n) type, with n=0, 1, 2 or 3 and T₁ representing            one of the following radicals: methyl, vinyl, alkyl,            alkynyl, nitrile, cycloalkyl, which may be C₃ or C₄, Z—O,            Z—CO, with Z═C₁-C₃ alkyl, or hal, hal representing F, Cl, Br            or I or a CCl₃ group,    -   or        -   an R₃—NH— group, R₃ then being chosen from radicals of            T₂-(CH₂)_(n) type, with n=0, 1 or 2, and T₂ representing one            of the following radicals: methyl, vinyl, ZO, ZO—CONH—,            —CH—(OZ)₂, ZCO, with Z═H or linear or branched C₁-C₄ alkyl,            NH₂, C₃ cycloalkyl, aryl, or substituted aryl, or R₂═H,    -   or        -   an R₄—CONH— group, R₄ then being a branched C₃-C₅ alkyl            radical,    -   or        -   R═Ar₂, Ar₂ being chosen from a phenyl, substituted phenyl or            benzodioxolyl radical.

Preferably, the invention relates, for use as medicaments, toimidazolone derivatives having an IC₅₀ of less than 1 μM andcorresponding to formula I in which:

-   -   R₁ represents H or CH₃    -   Ar₁ represents the radical

-   -   R₂ represents        -   an R₂—S— group, R₂ then being chosen from radicals of            T₁-(CH₂)_(n) type, with T₁=a methyl, alkynyl, nitrile, hal,            CH₃O, cyclopropyl or cyclobutyl radical, n=0, 1, 2 or 3,            “hal” representing a halogen atom or a CCl₃ group,    -   or        -   an R₃—HN— group, R₃ then being chosen from radicals of            T₂-(CH₂)_(n) type, with T₂=C₃ alkyl, OH, cyclopropyl,            phenyl, phenyl substituted with OH, OCH₃, COOH and OH,            CH₂OH, C(CH₃, OH), CH₂—CH₂OH, CH₂—COOH or benzodioxolyl, or            R₃═H, n=0, 1 or 2,    -   or        -   an Ar₂ group chosen from a para-hydroxyphenyl or            benzodioxolyl group.

In one preferred group of imidazolone derivatives of formula (I),

-   -   R represents R²S, R³HN, or Ar²;    -   R¹ represents H or a linear or branched C₁-C₅ alkyl radical;    -   R² represents H or a linear or branched C₁-C₅ alkyl radical,        where appropriate substituted with one or more OH, C₁-C₅ alkoxy,        (CH₂)_(n)—OH or (CH₂)_(n)—COOH radicals; or represents a cyclic        radical, where appropriate of the —(CH₂)_(n)— cycloalkyl type,        the cycloalkyl radical having 3 to 5 members and n=1-5, the        cyclic radical being, where appropriate, substituted with a        C₁-C₅ alkyl; or represents a (C₁-C₅)alkylenenitrile;        (C₁-C₅)alkylenevinyl; or C₁-C₅ alkynyl radical;    -   R³ represents a linear or branched C₁-C₅ alkyl radical, where        appropriate substituted with one or more C₁-C₅ alkoxy, OH, or        COOH radicals; or represents a cyclic radical, where appropriate        of the —(CH₂)_(n)— cycloalkyl type; or represents a phenyl        radical, where appropriate substituted with one or more —OH,        (CH₂)_(n)—OH; alkoxy or COOH; or a benzodioxolyl radical; or        represents a cyclic radical, where appropriate of the        —(CH₂)_(n)-cycloalkyl type, the cycloalkyl radical having 3 to 5        members, and n=1-5; or NH₂;    -   Ar¹ represents a benzodioxolyl radical;    -   Ar² represents a benzodioxolyl or phenyl radical, the latter        being, where appropriate, substituted with one or more —OH or        alkoxy.

In another preferred group of imidazolone derivatives of formula (I),

-   -   R represents R²S, R³HN, or Ar²;    -   R¹ represents H or a linear or branched C₁-C₅ alkyl radical;    -   R² represents a linear or branched C₁-C₅ alkyl radical, where        appropriate substituted with one or more OH, C₁-C₅ alkoxy or        (CH₂)_(n)—OH radicals; or represents a cyclic radical, where        appropriate of the —(CH₂)_(n)— cycloalkyl type, the cycloalkyl        radical having 3 to 5 members, and n=1-5; or represents a        (C₁-C₅)alkylenenitrile radical or a (C₁-C₅)alkylenevinyl        radical;    -   R³ represents a phenyl radical, where appropriate substituted        with one or more —OH, (CH₂)_(n)—OH; alkoxy; or a benzodioxolyl        radical; or represents a cyclic radical, where appropriate of        the —(CH₂)_(n)-cycloalkyl type, the cycloalkyl radical having 3        to 5 members, and n=1-5; or NH₂;    -   Ar¹ represents a benzodioxolyl radical;    -   Ar² represents a benzodioxolyl or phenyl radical, the latter        being, where appropriate, substituted with one or more —OH.

Particularly advantageously, the imidazolone derivatives used accordingto the invention are chosen from the following compounds in which, informula (I),

R═R₂S

R₂═CH₂C≡CH; R¹=Me; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂C≡N; R¹=Me; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂CH₂Cl; R¹=Me; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂CH₃; R¹═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂CH₂CH₃; R¹═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH(CH₃)₂; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂C\T; R¹═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂(CH₂)₂; R₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂CH₂OCH₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂T₁ with T₁=cyclopropyl; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₂═CH₂T₁ with T₁=cyclobutyl; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R═R₃NH

R₃═CH₂CH₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═CH₂CH₂OH; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═CH₂T₁ with T₁=cyclopropyl; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═CH₂CH₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=o-HO—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═C₆H₅; R₁=Me; Ar_(t)=1,3-benzodioxol-5-yl

R₃=p-HO—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-HO-m-HO₂C—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-m-OCH₂O—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-CH₃—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═HOCH₂CHOHCH₂; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-m-OCH₂CH₂O—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-CH₃O—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=m-HOCH₂—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=m-HOCH(CH₃)—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-HOCH₂CH₂—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃=p-HO₂CCH₂O—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

R₃═CH₂CH₂CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₃═CH₂T₁ with T₁=cyclopropyl; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₃═C₆H₅; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₃=p-HO—C₆H₄; R₁═H; Ar₁=1,3-benzodioxol-5-yl

R₃═H; R₁═H; Ar₁=p-HO-m-MeO—C₆H₃

R═Ar₂

Ar₂=p-HO—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

Ar₂=p-m-OCH₂O—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl

According to another aspect, the invention relates to novel imidazolonederivatives.

In fact, with the exclusion of the derivatives mentioned hereinafter,the derivatives of formula I above are new derivatives and, in thisrespect, are part of the field of the invention.

The invention thus relates, as novel products, to imidazolonederivatives, characterized in that they correspond to formula I of claim1, with the exclusion of the derivatives in which:

R═R₂S and

-   -   Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃ and R₂═CH₃, CH₃ CH₂,        CH₂═CH—CH₂, CH≡C—CH₂, CH₃—CH₂—OCO—CH₂, C₆H₄—CH₂    -   Ar₁=p, m-OCH₃; R₁═CH₃ and R₂═CH₃CH₂    -   Ar₁=m, m′-OCH₃C₆H₄; R₁═CH₃ and R₂═CH₃CH₂    -   Ar₁=1,3-benzodioxol-5-yl; R₁=n-butyl; R₂═CH₃, CH₃—CH₂,        CH₂═CH—CH₂, CH≡CH₂, C₆H₄—CH₂, p NO₂—C₆H₄—CH₂, CH₃CH₂OCO—CH₂    -   Ar₁=1,3-bromobenzodioxol-5-yl; R₁=n butyl; R₂═CH₃—CH₂    -   Ar₁=m, p OCH₃—C₆H₄; R₁=n butyl; R₂═CH₃CH₂    -   Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃; R₂═C₆H₅ or p-OHC₆H₄

R═R₃HN and

-   -   Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃; R₂═H, CH₃—(CH₂)₂, CH₃—(CH₂)₃,        p COOH—C₆H₄—CH₂    -   Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃—(CH₂)₃; R₂═CH₃—(CH₂)₂ or CH₃—        (CH₂)₃    -   Ar₁=1,3-benzodioxol-5-yl; R₁═C₆H₅, R₂═CH₃—(CH₂)₂    -   Ar₁=p OH, m-OCH₃—C₆H₄ or m, p OH—C₆H₄; R₁═H; R₂═H.

These novel derivatives, in the use thereof as medicaments, are alsopart of the invention.

The invention therefore relates to pharmaceutical compositionscomprising a therapeutically effective amount of the derivatives offormula (I) defined above.

As shown by the IC₅₀ values reported in the examples, the compoundsdefined above constitute potent inhibitors of the DYRK1A kinase and, inthis respect, are useful both as pharmacological tools for fundamentalresearch and as therapeutic agents for the treatment ofneurodegenerative diseases, in particular Alzheimer's disease and othertau pathologies, Pick's disease and trisomy 21.

The derivatives of formula I or the novel derivatives according to theinvention in fact constitute tools for studying the functions of DYRK1Ain various cell models, and the consequences of the expression thereofand of an abnormal activity. They constitute active ingredients ofmedicaments for countering the effects of the overexpression/abnormalactivation of DYRK1A in the pathological conditions above.

During the production of medicaments, the active ingredients, used intherapeutically effective amounts, are mixed with the carriers that arepharmaceutically acceptable for the method of administration selected.

Thus for oral administration, the medicaments are prepared in the formof gel capsules, tablets, sugar-coated tablets, capsules, pills, drops,and the like. Such medicaments may contain from 1 to 100 mg of activeingredient per unit.

For injectable (intravenous, subcutaneous, intramuscular)administration, the medicaments are in the form of sterile orsterilizable solutions. The doses per unit intake may range from 1 to 50mg of active ingredient. The daily dosage is chosen so as to obtain afinal concentration of at most 100 μM of imidazolone analog orderivative in the blood of the patient treated.

According to yet another aspect, the present invention also relates to amethod for synthesizing the imidazolone derivatives of formula I definedabove.

This method is characterized in that it comprises the use of anarylidene thiohydantoin derivative corresponding to formula 3

in which:R₁, R₂ and Ar₁ are as defined above.

According to one embodiment aimed at preparing the imidazolonederivatives of formula I in which R═R₂S, the method of the inventioncomprises reacting a thiohydantoin derivative 3 with a halogenatedderivative 3′ of formula

R₂X  (3′)

with X═Cl, Br or I

under conditions which make it possible to obtain an imidazolonederivative 4, according to scheme 4 below:

Advantageously, the reaction between the compounds 3 and 3′ is carriedout in an organic solvent, at a temperature of from 70 to 100° C., inparticular of 80° C., in the presence of carbonate.

In order to more particularly obtain derivatives of formula (I) in whichR₂ is an aryl radical, the method of the invention comprises reactingthe thiohydantoin derivative 3 with an arylboronic acid 7′ of formula

Ar₂B(OH)₂  (7′)

under conditions which give the derivatives of formula 8, according toscheme 1′:

Satisfactory conditions correspond to a reaction, under microwave, ofthioxohydantoin with boronic acid in the presence of Cu(AcO)₂, (withAc=acetyl) and of phenanthroline in an organic solvent such asdichloroethane.

The mixture is irradiated for from 50 to 100 min, in particular from 60to 90 min, at 70-90° C., in particular 80° C., with a maximum power ofapproximately 300 Watts.

According to one embodiment aimed at preparing the imidazolonederivatives of formula I in which R═R₃HN, the method of the inventioncomprises:

-   -   either reacting an imidazolone derivative as defined above 4        with an amine 4′ of formula

R₃—NH₂  (4′)

under conditions which make it possible to obtain the imidazolonederivative 5 of formula and according to scheme 2 below:

-   -   or reacting a hydantoin derivative 3 as defined above with an        amine 4′, according to scheme 3 below:

Preferably, the reaction according to scheme 3 is carried out in an oilbath and a microwave. In the procedure with the oil bath, the reactionmixture is heated to a temperature below the boiling point of the amine.When the procedure is carried out under microwave, the mixture isadvantageously irradiated for from 10 to 100 minutes at an appropriatetemperature and power.

The reaction according to scheme 3 is advantageously carried out in asolvent such as methanol in the presence of hydroperoxide.

According to one embodiment aimed at preparing the imidazolonederivatives of formula I in which R═R₄COHN, the method of the inventioncomprises reacting an imidazolone derivative 5 of formula

with an acid chloride 5′ of formula

R₄COCl  (5′)

under conditions which make it possible to obtain an imidazolonederivative 6, according to scheme 4 below:

The substituents in these various formulae are as defined above.

Appropriate conditions for carrying out the reaction between thesederivatives comprise the addition of triethylamine, and then of the acidchloride (5′) to a solution, in an organic solvent such as THF, of theimidazolone derivative 5.

This reaction is advantageously carried out at a temperature of theorder of 20 to 25° C.

In order to prepare the imidazolone derivatives of formula I in whichR═Ar₂, the method of the invention comprises reacting a thiohydantoinderivative of formula 3 with a boronic acid 7′

Ar₂B(OH)₂  (7′)

under conditions which make it possible to obtain an imidazolonederivative 7, according to scheme 5 below:

This reaction is advantageously carried out in the presence of acatalyst such as Pd(PPh₃)₄ and of CuTC (Copper Thiophene Carboxylate) inan anhydrous organic solvent such as anhydrous THF. This reaction isadvantageously carried out at a temperature of the order of 55 to 65° C.

More particularly preferably, the thiohydantoin derivative 3 is obtainedby reacting a thiohydantoin derivative of formula 2

with an aldimine derivative of formula 2′

Ar₁-CH═N-alk  (2′)

the substituents being as defined above and “alk” representing a C₃-C₅alkyl radical, according to scheme 6 below:

Advantageously, the reaction is carried out in an oil bath or undermicrowave.

In the oil bath procedure, the reactants are added to an organic solventand the reaction mixture is brought to reflux. A viscous oil whichcrystallizes rapidly is recovered after filtration and purified ifdesired.

Among the appropriate organic solvents, mention will be made ofacetonitrile.

In the microwave procedure, the mixture of thiohydantoin of formula 2and of aldimine of formula 2′ is placed in the microwave reactor,inserted into a microwave oven, where the mixture is irradiated, andthen, at the end of the reaction and after a return to ambienttemperature, the reaction product is recovered.

Appropriate conditions comprise a treatment of approximately 1 h at70-100° C., in particular 80° C., with a maximum power of 80-100 Watts,more especially of 90 Watts.

The aldimine 2′ is obtained, for example, starting from an aldehyde 2″Ar₁-CH═O and from propylamine 2″′ CH₃—(CH₂)₂—NH₂. This reaction isadvantageously carried out in a microwave reactor at a power of 300Watts for example at 20-80° C., in particular 25 to 60° C., for 2 to 5minutes, in particular 3 minutes, and then at 60-80° C. at a reducedpower of the order of 10 to 30%, in particular 20%.

The thiohydantoin derivative 2 is preferably obtained by reacting methylglycinate hydrochloride 1

CH₃O₂C—CH₂—NH₂, HCl  (1)

with an isothiocyanate 1′ of formula

R₁—N═C═S  (1′)

according to scheme 7 below:

Satisfactory reaction conditions comprise reacting 1 and 1′ in thepresence of triethylamine, in a solvent such as ether, at reflux.

The intermediate compounds in these various operational stages are noveland, in this respect, are also part of the field of the invention.

Other characteristics and advantages of the invention are given in thefollowing exemplary embodiments of the invention relating to thesynthesis of the imidazolone derivatives according to the invention.

By way of illustration, the experimental conditions for the reactionsdenoted A to H, summarized in FIG. 1, are reported in the experimentalsection which follows.

The IC₅₀ values in μM with respect to DYRK1A of compounds according tothe invention are subsequently given in table 2 in the section relatingto the assay of the DYRD1A kinase activity.

EXPERIMENTAL SECTION

TABLE 1

Reaction A:

General procedure: A mixture constituted of 7 mmol of isothiocyanate(R¹N═C═S), 7 mmol (0.88 g) of methyl glycinate hydrochloride 1, and 7mmol (0.97 ml) of triethylamine in 15 ml of ether is heated for 14 hoursat the reflux of the solvent with vigorous magnetic stirring. Aftercooling of the reaction medium to ambient temperature, the solvent iseliminated under reduced pressure on a rotary evaporator. Thetriethylamine hydrochloride is eliminated by precipitation from ethylacetate. After filtration through sintered glass with No. 4 porosity,the filtrate is concentrated on a rotary evaporator under reducedpressure and the expected product 2 is obtained. The latter issubsequently used without further purification.

Example of Compound 2 3-methyl-2-thioxoimidazolidin-4-one (R¹=Me)

Yield=95%, mp=170-172° C. ¹H NMR (200 MHz, CDCl₃, TMS) δ: 3.27 (s, 3H,NCH₃); 4.11 (s, 2H, —CH₂—); 7.64 (broad s, 1H, NH). ¹³NMR (75 MHz,CDCl₃, TMS) δ: 27.6 (NCH₃); 48.6 (—CH₂—); 171.6 (C═O); 185.4 (C═S).

Reaction B:

General oil bath procedure: Dichloromethane (20 ml), 6.9 mmol ofthiohydantoin 2, and then 6.9 mmol of freshly distilled aldimine(*) aresuccessively added to a round-bottomed flask equipped with a magneticbar. The reaction mixture is subsequently brought to the reflux ofdichloromethane and the reaction is monitored by thin layerchromatography on silica 60 F 254 (Merck). When the reaction iscomplete, the reaction medium is cooled to ambient temperature, and isthen dried over anhydrous MgSO₄. After filtration through pleated paper,the filtrate solvent is eliminated by evaporation under reduced pressureand a viscous oil which crystallizes rapidly at ambient temperature isobtained. The purification is carried out either by recrystallizationfrom pentane or, optionally, by chromatography on silica gel 60 F 254(Merck) with an appropriate solvent.

General microwave procedure: A mixture constituted of 10 mmol ofthiohydantoin 2 and 10 mmol (1 equivalent) of aldimine(*) is placed in acylindrical microwave reactor (Ø=4 cm). The reactor is then insertedinto a Synthewave 402 microwave oven (trademark Prolabo, Merck-Eurolabgroup) fitted with a blade stirrer system. The mixture is irradiated forone hour at 80° C. (3-minute hold) with a maximum power of 90 Watts(Prolabo microwave). After a return to ambient temperature, the reactionmixture is then concentrated on a rotary evaporator. A solution of achloroform/pentane mixture (1/2) is added to the evaporation residue.After trituration of this mixture, the insoluble solid is filteredthrough sintered glass with a No. 4 porosity and then dried underreduced pressure.

Example of Compound 3(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-3-methyl-2-thioxoimidazolidin-4-one(Ar¹=1,3-benzodioxol-5-yl, R¹=Me)

Yield=87%. Yellow powder, mp=253-255° C. ¹H NMR (300 MHz, DMSO-d₆)δ=3.18 (s, 3H, NCH₃); 6.09 (s, 2H, OCH₂O); 6.54 (s, 1H, C═CH); 6.96 (d,1H, J=8.1 Hz, H-5); 7.27 (d, 1H, J=8.1 Hz, H-6); 7.45 (s, 1H, H-2);12.22 (bs, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆) δ=27.6 (NCH₃); 102.1(OCH₂O); 109.1 (C-5); 109.8 (C-2); 113.7 (C═CH); 125.1 (C═CH); 126.9(C-6); 126.9 (C-1); 148.4 (C-4); 149.0 (C-3); 164.6 (C═O); 179.0 (C═S).HRMS, m/z: 262.0409 (calculated for C₁₂H₁₀N₂O₃S, 262.0412).

(*) General procedure for the synthesis of aldimines: 20 mmol ofaldehyde and 40 mmol (3.28 ml) of propylamine are successively weighedout into a quartz reactor. This reaction medium is heated in theSynthewave 402 microwave reactor (P_(max•)=300 W, trademark Prolabo,Merck-Eurolab group) according to the following programming (from 25 to60° C. for 3 minutes then at 60° C. for 30 minutes with a power of 20%).The excess propylamine is eliminated on a rotary evaporator underpartial vacuum and then the evaporation residue (solid state) issolubilized in dichloromethane (10 ml/g of product); the organicsolution is then dried over MgSO₄, and filtered through filter paper.The filtrate is concentrated on a rotary evaporator under reducedpressure.

Aldimine Example N-[(1,3)-benzodioxol-5-ylmethylene]-N-propylamine(Ar¹=1,3-benzodioxol-5-yl)

Yield=97%. Yellow powder. ¹H NMR (200 MHz, CDCl₃) δ: 0.90 (t, 3H, J=7.3Hz, NCH₂CH₂CH₃); 1.64 (st, 2H, J=7.2 Hz, NCH₂CH₂CH₃); 3.47 (t, 2H, J=6.9Hz, NCH₂CH₂CH₃); 5.90 (s, 2H, OCH₂O); 6.71 (d, 1H, J=7.9 Hz, H-5); 7.02(dd, 1H, J=1.3; 7.9 Hz, H-6); 7.37 (d, 1H, J=1.4 Hz, H-2); 8.10 (s, 1H,N═CH). ¹³C NMR (75 MHz, CDCl₃) δ: 12.2 (CH₃); 24.5 (CH₂CH₃); 63.7(NCH₂); 101.8 (OCH₂O); 107.0 (C-3); 108.4 (C-6); 124.5 (C-2); 131.6(C-1); 148.6 (C-5); 150.0 (C-4); 160.3 (N═CH).

Reaction C:

General procedure: The 5-arylidene thiohydantoin 3 (3.1 mmol, 1 eq.), 20ml of acetonitrile, the halogenated derivative R²X with X═Cl, Br or I(3.1 mmol, 1 eq.) and 0.21 g of K₂CO₃ (1.5 mmol, 0.5 eq.) aresuccessively added to a round-bottomed flask. The reaction mixture isheated at 80° C. for 14 hours with vigorous magnetic stirring. Aftercooling to ambient temperature, the acetonitrile is eliminated on arotary evaporator under reduced pressure. 20 ml of ether are added tothe crude reaction medium. After filtration of the insoluble inorganicproducts, under a partial vacuum, through sintered glass with a no. 4porosity, the filtrate is dried over magnesium sulfate and then filteredthrough pleated paper. The filtrate solvent is eliminated on a rotaryevaporator under reduced pressure and the expected imidazolone 4 isobtained in the form of a powder.

Example of Compound 4[(Z)-(4-Benzo[1,3]dioxol-5-ylmethylene-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-ylsulfanyl)]acetate(Ar¹=1,3-benzodioxol-5-yl, R¹=Me, R²═CH₂CO₂Et)

Yield=92%. Yellow powder, mp=172-174° C. ¹H NMR (300 MHz, CDCl₃) δ: 1.26(t, 3H, J=7.1 Hz, OCH₂CH₃ ); 3.12 (s, 3H, NMe); 4.02 (s, 2H, SCH₂ );4.23 (q, 2H, J=7.1 Hz, OCH₂ CH₃); 5.96 (s, 2H, OCH₂ O); 6.80 (d, 1H,J=8.1 Hz); 6.84 (s, 1H, ═CH); 7.52 (dd, 1H, J 8.1; 1.3 Hz); 7.96 (d, 1H,J=1.3 Hz). ¹³C NMR (75 MHz, CDCl₃) δ: 14.1 (qm, J=128 Hz, OCH₂ CH₃);26.6 (q, 144 Hz, NMe); 32.9 (t, J=144 Hz, SCH₂); 62.3 (tq, J 148; 4.6Hz, OCH₂); 101.5 (t, J=174 Hz, OCH₂O); 108.4 (d, J=165 Hz); 110.8 (dt, J168; 6.9 Hz); 124.6 (dt, J 156; 4.1 Hz); 128.4 (dt, J 162; 6.0 Hz);128.9 (d, J=7.6 Hz); 136.6 (s); 148.0 (m, ═C—O); 149.3 (m, ═C—O); 162.0(m, C-2); 168.0 (m, C═O(CO₂Et)); 169.7 (m, C-4). HRMS, m/z: 348.0791(calc. for C₁₆F1₁₆N₂O₅S: 348.0780).

Reaction D:

Microwave procedure: A mixture constituted of(5Z)-5-arylidene-2-alkylthio-3,5-dihydroimidazol-4-one 4 (4 mmol, 1 eq.)and of 5-20 mmol of aminoalcohol R³—NH₂ (1.5 to 5 equivalents) is placedin a cylindrical microwave reactor (Ø=4 cm). The reactor is theninserted into the Synthewave 402 microwave oven (trademark Prolabo,Merck-Eurolab group) fitted with a blade stirrer system. The mixture isirradiated for from 15 minutes to 90 minutes at an appropriatetemperature and an appropriate power. After a return to ambienttemperature, the reaction mixture is then concentrated on a rotaryevaporator. Ethanol (1 ml/g of product) is added to the evaporationresidue. After trituration of the mixture from ethanol, the insolublesolid is filtered off through sintered glass with a no. 4 porosity andthen dried under reduced pressure. The latter is optionallyrecrystallized from ethanol.

Oil bath procedure: A suspension constituted of(5Z)-5-arylidene-2-alkylthio-3,5-dihydroimidazol-4-one 4 (4 mmol, 1 eq.)and of aliphatic amine (40 mmol, 10 eq.) is mixed with vigorous magneticstirring and heated at a temperature 10° C. below the boiling point ofthis amine (T_(exp•)=BP_(amine)−10° C.) for 3 to 7 days. After a returnto ambient temperature, the volatile products are eliminated underreduced pressure and ether (−10 ml) is added to the reaction medium.Next, the products that are insoluble in ether are collected byfiltration through sintered glass with a no. 4 porosity. The residualsolvent of the compound 5 is eliminated under a partial vacuum in adesiccator for two hours, and the expected 2-aminoimidazolone 5 isobtained in the form of a yellow powder.

Example of 2-aminoimidazolone 5(5Z)-5-Benzo[1,3]dioxol-5-ylmethylene-3-methyl-2-propylamino-3,5-dihydroimidazol-4-one(Ar¹=1,3-benzodioxol-5-yl, R¹=Me, R³═CH₂CH₂CH₃)

Yield: 48%. Yellow powder, mp=190-192° C. ¹H NMR (300 MHz, CDCl₃) δ 1.02(t, 3H, J=7.4 Hz); 1.74 (sext, 2H, J=7.3 Hz, NHCH₂CH₂ ); 3.11 (s, 3H,NMe); 3.54 (t, 2H, J=6.2 Hz, NHCH₂ C₂H₅); 4.95 (bs, 1H, NH); 5.98 (s,2H); 6.62 (s, 1H, ═CH); 6.81 (d, 1H, J=8.1 Hz); 7.34 (dd, 1H, J 8.1; 1.4Hz); 7.99 (d, 1H, J=1.2 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 11.5 (qt, J 126;4.0 Hz, NHC₂HMe); 22.8 (tq, J 135; 3.7 Hz, NHCH₂ CH₂); 25.2 (q, J 140Hz, NMe); 43.7 (tq, J 122; 7.0 Hz, NHCH₂); 101.1 (t, J=173 Hz, C-7′);108.4 (d, J 164 Hz, C-2′); 110.3 (dt, J 166; 7.1 Hz, C-6); 116.8 (dt, J157; 3.5 Hz); 126.1 (dt, J 163; 6.2 Hz, C-6′); 130.2 (d, J 7.8 Hz,C-5′); 138.1 (s, C-5); 147.6 (m, C-3′); 147.7 (m, C-4′); 157.2 (m, C-4);170.4 (sm, C-2). HRMS, m/z: 287.1279 (calc. for C₁₅H₁₇N₃O₃: 287.1270).

Reaction E:

General procedure: Triethylamine (2 equiv.) and then acid chloride (1.5equiv.) are added, at 0° C., to a solution of 0.2 mmol of2-aminoimidazolone 5 (R³═H, R¹=Me) in THF (2 ml). The reaction mixtureis stirred at 25° C. for 12 h. The solution is then evaporated underreduced pressure and the residue is purified by flash chromatography onsilica gel using a mixture of EtOAc/cyclohexane (9/1) as eluant.

Example of Compound 6N-[(4Z)-4-Benzo[1,3]dioxol-5-ylmethylene-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl]-2,2-dimethylpropanamide(Ar¹=1,3-benzodioxol-5-yl, R¹=Me, R₄═C(CH₃)₃)

Yield: 50%. Yellow powder, mp=145-147° C. ¹H NMR (300 MHz, CDCl₃):δ=1.28 (s, C(CH₃)₃, 9H), 3.24 (s, CH₃, 3H), 6.05 (s, OCH₂O, 2H), 6.76(s, ═CH, 1H), 6.92 (d, J=8.0 Hz, H_(ar), 1H), 6.93 (s, H_(ar), 1H), 7.01(d, J=8.0 Hz, H_(ar), 1H). ¹³C NMR (75 MHz, CDCl₃): δ=25.6 (C(CH₃)₃),26.7 (C(CH₃)₃), 39.7 (NCH₃), 101.6 (OCH₂O), 108.5, 111.2, 128.1, 129.1,142.5, 146.5, 149.7, 161.8, 171.2, 179.1. HRMS, m/z=329.1377 (calculatedfor C₁₇H₁₉N₃O₄ 329.1375).

Reaction F:

General procedure: 3 equivalents of tert-butyl hydroperoxide TBHP(aqueous solution at 70%) and then 20 equivalents of amine are added toa solution of 3 (0.80 mmol) in MeOH (20 ml). The reaction mixture isstirred at 25° C. for three days. The solution is then evaporated underreduced pressure and the residue is purified by flash chromatography onsilica gel using a mixture of CH₂Cl₂/MeOH (94/6) as eluant.

Example of Compound 5(5Z)-5-Benzo[1,3]dioxol-5-ylmethylene-2-ethylamino-3,5-dihydro-4H-imidazol-4-one(Ar¹=1,3-benzodioxol-5-yl, R³=Et, R¹═H)

Yield=40%. Yellow powder, mp=222-224° C. ¹H NMR (300 MHz, DMSO-d₆):δ=1.17 (t, J=6.9 Hz, CH₃, 3H), 3.34 (m, CH₂, 2H), 6.02 (s, OCH₂O, 2H),6.23 (s, ═CH, 1H), 6.90 (d, J=8.1 Hz, H_(ar), 1H), 7.20 (br.s, NH, 1H),7.38 (d, J=8.1 Hz, H_(ar), 1H), 7.93 (s, H_(ar), 1H), 10.68 (br.s, NH,1H). ¹³C NMR (75 MHz, DMSO-d₆): δ=15.5 (CH₃), 36.4 (NHCH₂), 101.4(OCH₂O), 108.7, 109.8, 125.3, 131.0, 140.6, 146.9, 147.6, 160.2, 174.5.HRMS, m/z=259.0959 (calculated for C₁₃H₁₃N₃O₃ 259.0957).

Reaction G:

General procedure: A suspension constituted of 5 mmol of aldimineAr¹CH═N—Pr, 5 mmol of thiohydantoin 2 (R¹=Me, Bu, Ph), 7.5 mmol ofhaloalkane R²X, 0.345 g (2.5 mmol) of potassium carbonate and,optionally, 1.25 g (7.5 mmol) of KI (if use is made of a halogenatedderivative R²X with X═Br or Cl) in 10 ml of acetonitrile is heated for14 hours at a temperature close to the boiling point of the haloalkaneR²X (T_(exp•)=Bp_(R2X)−10° C.). The reaction solvent is then eliminatedon a rotary evaporator under reduced pressure. The solid obtained afterevaporation is triturated with dichloromethane (10 ml/g of product) andthen the insoluble inorganic salts are eliminated by filtration throughpaper. After evaporation of the filtrate, the crude reaction medium istreated (1 g/10 ml) with a mixture of pentane/ethanol (1/1). Theexpected product 4 precipitates, and is then collected through sinteredglass with a no. 4 porosity and dried in a desiccator under a partialvacuum.

Example of Compound 4(5Z)-5-(1,3-benzodioxol-5-ylmethylene)-3-methyl-2-(ethylthio)-3,5-dihydro-4H-imidazol-4-one (Ar¹=1,3-benzodioxol-5-yl, R¹=Me,R³=Et)

Yield=92%. Orangey-yellow powder, mp=152-154° C. ¹H NMR (300 MHz, CDCl₃)δ: 1.55 (t, 3H, J=7.4 Hz, SCH₂CH₃); 3.17 (S, 3H, NCH3); 3.40 (q, 2H,J=7.4 Hz, SCH₂CH₃); 6.00 (s, 2H, OCH₂O); 6.82 (d, 1H, J=8.1 Hz, H-5);6.83 (s, 1H, ═CH); 7.37 (dd, 1H, J=8.1; 1.0 Hz, H-6); 8.05 (s, 1H, H-2).¹³C NMR (75 MHz, CDCl₃) δ: 14.7 (SCH₂CH₃); 25.6 (SCH₂CH₃); 26.9 (NCH₃);101.8 (OCH₂O); 108.8 (C-5); 111.2 (C-2); 124.0 (═CH); 128.4 (C-6); 129.5(C-1); 137.5 (NC═C); 148.3 (C-4); 149.5 (C-3); 164.1 (C—S); 170.3 (C═O).HRMS, m/z=290.0730 found (calculated for C₁₄H₁₄N₂O₃S: 290.0725, M⁺⁺).

Reaction H:

General procedure: A solution constituted of (5Z)-5-arylidenethiohydantoin 3 (1 equivalent), of boronic acid Ar²B(OH)₂ (1.5equivalents), of Pd(PPh₃)₄ (5 mol %) and of CuTC (3 equivalents) inanhydrous THF (0.06 M) is introduced into a Schlenk tube. The reactionmixture is brought to the reflux of THF overnight with vigorous magneticstirring. After a return to ambient temperature, the reaction medium isextracted with dichloromethane (twice). The organic phase is washed witha solution of sodium hydrogen sulfate (1M), and then with a saturatedsolution of sodium chloride and, finally, with a solution of sodiumhydrogen carbonate (1M). The organic phase is dried over MgSO₄ andfiltered through paper, and the filtrate is concentrated on a rotaryevaporator under vacuum. The evaporation residue is solubilized underhot conditions in diethyl ether. After cooling, the crystals arecollected by filtration through sintered glass with a no. 4 porosity,under a partial vacuum, and then purified by silica gel chromatographywith a cyclohexane/ethyl acetate mixture (70/30) as eluant. Thechromatography fraction is then concentrated on a rotary evaporator anddried under a partial vacuum, resulting in the expected product 7.

Example of Compound 7(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-3-methyl-2-phenyl-3,5-dihydro-4H-imidazol-4-one(Ar¹=1,3-benzodioxol-5-yl, R¹=Me, Ar²═C₆H₅)

Yield=46%. Yellow powder, mp=209-211° C. ¹H NMR (300 MHz, CDCl₃): δ=3.35(s, 3H, NCHO; 6.01 (s, 2H, OCH₂O); 6.84 (d, 1H, J=8.1 Hz, H-5′); 7.16(s, 1H, C═CH); 7.47 (dd, 1H, J=8.1 Hz, J=1.2 Hz, H-6′); 7.53 (m, 3H,H-3″, H-4″); 7.84 (dd, 2H, J=7.4 Hz, J=2.2 Hz, H-2″); 8.14 (d, 1H, J=1.2Hz, H-2′). ¹³C NMR (75 MHz, CDCl₃) δ=29.1 (NMe); 101.5 (OCH₂O); 108.5(C-5′); 111.5 (C-2′); 128.7 (C-2″); 128.8 (C-3″); 128.8 (C═CH); 129.0(C-6′); 129.4 (C-1″); 131.4 (C-4″); 137.5 (C═CH); 137.5 (C-1′); 148.1(C-3′); 149.7 (C-4′); 161.4 (C═N); 171.6 (C═O). HRMS, m/z: 306.0995(calculated for C₁₈H₁₄N₂O₃: 306.10044).

Reaction I:

General procedure: 0.4 mmol of (5Z)-5-arylidene thiohydantoin 3, 1.6mmol (4 equivalents) of boronic acid, 0.4 mmol (1 equivalent) of CuOAc₂,0.8 mmol (2 equivalents) of phenanthroline and 4 ml of dichloroethaneare placed in a cylindrical microwave reactor (Ø=2.8 cm). This reactoris then inserted into the microwave oven fitted with a blade stirrersystem. The mixture is irradiated for 60 to 90 minutes at 80° C.(2-minute hold) with a maximum power of 300 Watts (Prolabo microwave).After cooling to ambient temperature, the reaction mixture is thenconcentrated on a rotary evaporator under a partial vacuum. The expectedproduct 8 is purified on alumina gel, elution being carried out with apentane/ethyl acetate mixture (85/15), followed by washing with pentane.

Example of Compound 8(5Z)-5-(1,3-Benzodioxol-5-ylmethylene)-3-methyl-2-(phenylthio)-3,5-dihydro-4H-imidazol-4-one(Ar¹=1,3-benzodioxol-5-yl, R¹=Me, Ar²═C₆H₅)

Yield: 49%. Yellow powder, mp=171-173° C. ¹H NMR (300 MHz, Acetone-d₆):δ=3.22 (s, 3H, NCH₃); 6.03 (s, 2H, OCH₂O); 6.77 (s, 1H, C═CH); 6.82 (d,1H, J=8.1 Hz, H-5′); 7.36 (dd, 1H, J=8.1 Hz, J=1.2 Hz, H-6′); 7.56 (d,1H, J=1.7 Hz, H-2′); 7.58 (d, 2H, J=1.7 Hz, H-2″); 7.78 (m, 2H, H-3″);7.83 (d, 1H, J=1.3 Hz, H-4″). ¹³C NMR (75 MHz, DMSO-d₆) δ=26.6 (NMe);101.5 (OCH₂O); 108.3 (C-5′); 109.9 (C-2′); 123.4 (C═CH); 125.1 (C-1″);128.3 (C-6′); 128.4 (C-1′); 129.4 (C-2″); 130.0 (C-4″); 134.8 (C-3″);136.5 (C═CH); 147.5 (C-4′); 148.9 (C-3′); 162.8 (C═N); 168.5 (C═O).HRMS, m/z: 338.0738 (calculated for C₁₈H₁₄N₂O₃S: 338.07251).

Assaying of the Kinase Activity of DYRK1A Biochemical Reagents

Sodium ortho-vanadate, EGTA, Mops, β-glycerophosphate, phenylphosphate,dithiothreitol (DTT), glutathione-agarose, glutathione,nitrophenylphosphate and myelin basic protein were obtained from SigmaChemicals. [γ-³³P]-ATP comes from Amersham.

Preparation of the DYRK1A Kinase and Enzyme Assay for the ActivityThereof

Rat recombinant DYRK1A was expressed in E. coli as a GST fusion protein.It was purified by affinity chromatography on beads of immobilizedglutathione (elution with free glutathione). The kinase activity wasassayed in buffer C (60 mM β-glycerophosphate, 15 mMp-nitrophenylphosphate, 25 mM Mops (pH 7.2), 5 mM EGTA, 15 mM MgCl₂, 1mM DTT, 1 mM sodium vanadate, 1 mM phenylphosphate), with 1 mg of myelinbasic protein/ml, in the presence of 15 μM [γ-³³P]-ATP (3.000 Ci/mmol;10 mCi/ml) in a final volume of 30 μL. After incubation at 30° C. for 30min, 25-μL aliquots of supernatant were spotted onto Whatman P81phosphocellulose filters and the filters were washed five times in asolution of phosphoric acid (10 ml/L water). The radioactivityincorporated into the substrate, retained on the moist filters, was thencounted in the presence of ACS scintillation fluid (Amersham). Thecontrol values were subtracted and the activities were expressed as % ofthe maximum value, i.e. the value obtained in the absence of inhibitors.The IC₅₀ values were calculated from dose-response curves and are givenin μM.

The results are given in table 2 hereinafter:

TABLE 2 3

IC₅₀ Molecule DYRK1A Reaction Reference (μM) R¹ Ar¹ used JR361 >10 n-Bu

B JR370 >10 Ph

B FC071 2.6 H

B ST341 >10 Me

B ST279 >10 H

B ST089 >10 Me

B ST076 >10 Me

B ST169 >10 Me

B ST202 >10 H

B ST227 66 H

B ST229 65 H

B ST197 >10 Me

B ST195 >10 H

B ST223 >10 Me

B References: 1: Microwave mediated solventless synthesis of newderivatives of marine alkaloid Leucettamine B. Jean René Chérouvrier,François Carreaux, Jean Pierre Bazureau Tetrahedron Letters 2002, 43,3581-3584. 2: The isolation and synthesis of polyandrocarpamines A andB. Two new 2-aminoimidazolone compounds from the Fiijian ascidian,Polyandrocarpa sp. Rohan A. Davis, William Aalbersberg, Semisi Meo,Rosan Moreira da Rocha, Chris M. Ireland Tetrahedron 2002, 58,3263-3269.

4

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ SR² Ar¹ used ST099 6.8Me SMe

C SB26 1.4 Me SEt

G ST094 1.8 Me Sn-Pr

C ST097 1.3 Me Si-Pr

C SB14 3.4 Me

G SB16 0.9 Me

G ST211 0.47 Me

C ST381 0.44 Me SCH₂CH₂Cl

C ST101 2.3 Me Sn-Bu

C ST102 1.5 Me

C SA197 2.5 Me

C JR404 5.8 Me

C SB28 5.7 Me SBn

G ST342 >10 Me SEt

C ST091 >10 Me SEt

C ST078 6.7 Me SMe

C JR159 >10 Me SMe

C ST170 >10 Me SEt

C SB55 >10 Me SEt

G JR161 >10 Me SMe

C SB56 >10 Me SEt

G JR158 >10 Me SMe

C JR160 >10 Me SMe

C JR162 >10 Me SMe

C FB08 >10 Me SEt

C FB14 >10 Me Sn-Pr

C FB17 >10 Me Sn-Bu

C JR448 >10 n-Bu SMe

C SB05 >10 n-Bu SEt

G SB25 >10 n-Bu

G SB22 >10 n-Bu

G SB10 >10 n-Bu SBn

G SB60 >10 n-Bu

G SB80 >10 n-Bu SEt

G SB58 >10 n-Bu SEt

G JR411 >10 Ph

C ST105 0.68 H SMe

C ST120 0.44 H SEt

C ST122 0.44 H Sn-Pr

C ST135 0.46 H Si-Pr

C ST209 0.17 H

C ST124 0.59 H Sn-Bu

C ST164 0.65 H

C ST130 0.5 H

C ST142 0.78 H

C ST240 2.6 H SEt

C ST286 >10 H SEt

C ST280 >10 H SEt

C 5

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ NHR³ Ar¹ used FC077 4.7Me NH₂

F FC084 2.7 Me NHMe

F FC088 0.9 Me NHEt

F FCJR405 2.3 Me NHn-Pr

D Oil bath FCJR232 1.3 Me NHi-Pr

D Oil bath FCFD13 1.6 Me

D Oil bath MADE40 0.73 Me NHCH₂CH₂OH

D Microwave MADE26 >10 Me

D Microwave MADE47 0.79 Me

D Microwave MADE24 >10 Me

D Microwave IA24 >10 Me NHAc

E FCJR457 1.8 Me NHn-Bu

D Oil bath FCFD24 >10 Me NHi-Bu

D Oil bath FC107 0.98 Me

F SA142 1.3 Me

D Oil bath FC103 1.2 Me

F ST025 1.7 Me NHi-Am

D Oil bath MADE23 3 Me

D Microwave MADE10 1.4 Me

D Microwave MADE9 0.69 Me

D Microwave MADE32 0.4 Me NHC₆H₅

D Microwave MADE8 0.38 Me

D Microwave MADE33 0.94 Me

D Microwave MADE30 0.37 Me

D Microwave MADE29 0.19 Me

D Microwave MADE39 0.27 Me

D Microwave MADE37 0.23 Me

D Microwave MADE36 0.26 Me

D Microwave MADE42 0.43 Me

D Microwave MADE35 0.42 Me

D Microwave MADE34 0.86 Me

D Microwave FC097 1.4 Me NHBn

F MADE12 4.6 Me

D Microwave 6

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ NHCOR⁴ Ar¹ used IA32 15Me

E IA31 3.4 Me

E IA33 >10 Me

E IA25 >10 Me

E IA35 >10 Me

E 5

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ NHR³ Ar¹ used ST092 >10Me NHn-Pr

D Oil bath FCFD14 >10 Me NHn-Pr

D Oil bath FC104b >10 Me NHi-Pr

D Oil bath FCFD11 >10 Me NHn-Pr

D Oil bath FCFD08 >10 Me NHn-Pr

D Oil bath FC095 >10 Me NHi-Pr

D Oil bath FC092 >10 Me NHn-Pr

D Oil bath FC109 >10 Me NHi-Pr

D Oil bath SA164 >10 n-Bu

D Microwave JR442 >10 n-Bu NHn-Pr

D Oil bath FCJR464 >10 n-Bu NHn-Bu

D Oil bath JR445 >10 Ph NHn-Pr

D Oil bath FC085 1.7 H NHMe

F FC090 1.1 H NHEt

F FC126 0.89 H NHn-Pr

F MADE44 0.071 H

D Microwave MADE48 0.084 H

D Microwave FC114 0.5 H

F ST325 0.17 H NH₂

F ST326 >10 H NH₂

F ST033 0.3 Me

F 7

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ Ar² Ar¹ used NL39 3.2 MePh

H NL96 0.43 Me C₆H₅-pOH

H NL88A 0.22 Me

H 8

IC₅₀ Molecule DYRK1A Reaction reference (μM) R¹ SAr² Ar¹ used ST379 1.9Me

I ST385 >10 Me

I References: 1: Microwave mediated solventless synthesis of newderivatives of marine alkaloid Leucettamine B. Jean René Chérouvrier,François Carreaux, Jean Pierre Bazureau Tetrahedron Letters 2002, 43,3581-3584. 2: Parallel solution phase synthesis of2-alkylthio-3,5-dihydro-4H-imidazol-4-one by one-pot three componentdomino reaction. Stéven Renault, Sarah Bertrand, François Carreaux*,Jean Pierre Bazureau*. Journal of Combinatorial Chemistry 2007, 9,accepted for publication (awaiting authorization for ACS in ASAP). 3:Synthesis of the marine alkaloid Leucettamine B Nathalie Roué, IanBergman Tetrahedron 1999, 55, 14729-14738. 4: The isolation andsynthesis of polyandrocarpamines A and B. Two new 2-aminoimidazolonecompounds from the Fidjian ascidian, Polyandrocarpa sp. Rohan A. Davis,William Aalbersberg, Semisi Meo, Rosan Moreira da Rocha, Chris M.Ireland Tetrahedron 2002, 58, 3263-3269.

1. An imidazolone derivative for use as a medicament, characterized inthat said derivative corresponds to formula (I)

in which: R₁ represents H, a linear or branched, optionally substituted,C₁ to C₅ alkyl radical; an aryl group, or a 5- or 6-memberedheterocyclic group, the aryl group and the heterocyclic group optionallycomprising one or more substituents, which may be identical ordifferent, occupying any positions; Ar₁ represents an aryl group withoptionally one or more substituents, it being possible for two adjacentsubstituents to form a 5- or 6-membered ring, this ring being, whereappropriate, substituted; or an aromatic heterocycle with optionally oneor more substituents and/or condensed with a 5- or 6-membered aromaticring, the heteroatom being chosen from N, S and O; R represents R₂—S—,R₃—HN—, R₄COHN or Ar₂, with R₂=a linear, branched or cyclic C₁-C₅ alkylradical; a vinyl or vinyl(C₁-C₅)alkyl radical, a nitrile ornitrile(C₁-C₅)alkyl radical, or an aryl or benzyl radical, said radicalsbeing optionally substituted on one or more carbon atoms with one ormore groups, which may be identical or different, occupying anypositions, it being possible for two adjacent substituents to form a 5-or 6-membered ring, this ring being, where appropriate, substituted,R₃=the meanings given above and may also represent H; Ar₂ representing asubstituted or unsubstituted aryl radical, it being possible for twoadjacent substituents to form a 5 or 6-membered ring, this ring beingoptionally substituted.
 2. The derivative as claimed in claim 1,characterized in that the aryl group represents a phenyl or naphthylradical and the heterocycle is a 5- or 6-membered ring with N, O and/orS as heteroatom(s), the substituents of R₁, Ar₁, Ar₂ and R are chosenfrom: OH, OZ, COH, COZ, COON, COOZ, NH₂, NHalk., N(alk.)₂, NHCOOH,NHCOOZ, Z representing a linear or branched C₁-C₅ alkyl, aryl, benzyl,substituted benzyl or aryl, or benzodioxolyl radical, one or morehalogens and/or a CCl₃ group, and alk. representing a C₁-C₃ alkylradical.
 3. The derivative as claimed in claim 1, characterized in thatit has an IC₅₀ of less than 5 μM with respect to DYRK1A.
 4. Thederivative as claimed in claim 3, characterized in that it has an IC₅₀of less than 5 μM and corresponds to formula I above in which: R₁represents a C₁-C₃ alkyl radical or a hydrogen atom, and/or an arylradical Ar₁ is chosen from

R represents an R₃—S— group, R₃ then being chosen from radicals ofT₁-(CH₂)_(n) type, with n=0, 1, 2 or 3 and T₁ representing one of thefollowing radicals: methyl, vinyl, alkyl, alkynyl, nitrile, cycloalkyl,which may be C₃ or C₄, Z-0, Z—CO, with Z═C₁-C₃ alkyl, or hal, halrepresenting F, Cl, Br or I or a CCl₃ group, or an R₄—NH— group, R₄ thenbeing chosen from radicals of T₂-(CH₂)_(n) type, with n=0, 1 or 2, andT₂ representing one of the following radicals: methyl, vinyl, ZO,ZO—CONH—, —CH—(OZ)₂, ZCO, with Z═H or linear or branched C₁-C₄ alkyl,NH₂, C₃ cycloalkyl, aryl or substituted aryl, or R₂═H, or an R₂—CONH—group, R₂ then being a branched C₃-C₅ alkyl radical, or Y═Ar₂, Ar₂ beingchosen from a phenyl, substituted phenyl or benzodioxolyl radical. 5.The derivative as claimed in claim 3, characterized in that it has anIC₅₀ of less than 1 μM and corresponds to formula (I) in which: R₁represents H or CH₃ Ar₁ represents the radical

R₂ represents an R₂—S— group, R₂ then being chosen from radicals ofT₁-(CH₂)_(n) type, with T₁=a methyl, alkynyl, nitrile, hal, CH₃O,cyclopropyl or cyclobutyl radical, n=0, 1, 2 or 3, “hal” representing ahalogen atom or a CCl₃ group, or an R₃—HN— group, R₃ then being chosenfrom radicals of T₂-(CH₂)_(n) type, with T₂=C₃ alkyl, OH, cyclopropyl,phenyl, phenyl substituted with OH, OCH₃, COOH and OH, CH₂OH, C(CH₃,OH), CH₂—CH₂OH, CH₂—COOH or benzodioxolyl, or R₂═H, n=0, 1 or 2, or anAr₂ group chosen from a para-hydroxyphenyl or benzodioxolyl group. 6.The derivative as claimed in claim 3, characterized in that it is chosenfrom the derivatives of formula (I) in whichR═R₂S R₂═CH₂C≡CH; R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₂═CH₂C≡N; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₂═CH₂CH₂Cl; R₁=Me; Ar₁=1,3-benzodioxol-5-ylR₂═CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl R₂═CH₂CH₃; R₁═H;Ar₁=1,3-benzodioxol-5-yl R₂═CH₂CH₂CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-ylR₂═CH(CH₃)₂; R₁═H; Ar₁=1,3-benzodioxol-5-yl R₂═CH₂CH≡N; R₁═H;Ar₁=1,3-benzodioxol-5-yl R₂═CH₂(CH₂)₂CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-ylR₂═CH₂CH₂OCH₃; R₁═H; Ar₁=1,3-benzodioxol-5-yl R₂═CH₂T₁ withT₁=cyclopropyl; R₁═H; Ar₁=1,3-benzodioxol-5-yl R₂═CH₂T₁ withT₁=cyclobutyl; R₁═H; Ar₁=1,3-benzodioxol-5-ylR═R₃NH R₃═CH₂CH₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃═CH₂CH₂OH; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃═CH₂T₁ with T₁=cyclopropyl; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃═CH₂CH₃; R₁=Me; Ar₁=1,3-benzodioxol-5-ylR₃=o-HO—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃═C₆H₅; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃=p-HO—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-ylR₃=p-HO-m-HO₂C—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃=p-m-OCH₂O—C₆H₃;R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃=p-CH₃—C₆H₄; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃═HOCH₂CHOHCH₂; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃=p-m-OCH₂CH₂O—C₆H₃; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃=p-CH₃O—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-ylR₃=m-HOCH₂—C₆H₄; R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃=m-HOCH(CH₃)—C₆H₄;R₁=Me; Ar₁=1,3-benzodioxol-5-yl R₃=p-HOCH₂CH₂—C₆H₄; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃=p-HO₂CCH₂O—C₆H₄; R₁=Me;Ar₁=1,3-benzodioxol-5-yl R₃═CH₂CH₂CH₃; R₁═H; Ar₁=1,3-benzodioxol-5-ylR₃═CH₂T₁ with T₁=cyclopropyl; R₁═H; Ar₁=1,3-benzodioxol-5-yl R₃═C₆H₅;R₁═H; Ar₁=1,3-benzodioxol-5-yl R₃=p-HO—C₆H₄; R₁═H;Ar₁=1,3-benzodioxol-5-yl R₃═H; R₁═H; Ar₁=p-HO-m-MeO—C₆H₃R═Ar₂ Ar_(e)=p-HO—C₆H₄, R₁=Me; Ar₁=1,3-benzodioxol-5-ylAr₂=p-m-OCH₂O—C₆H₃; R₁=Me; Ar₁=1,3-benzodioxol-5-yl.
 7. A novelimidazolone derivative, characterized in that it corresponds to formulaI of claim 1, with the exclusion of the derivatives in which: R═R₂S andAr₁=1,3-benzodioxol-5-yl; R₁═CH₃ and R₂═CH₃, CH₃CH₂, CH₂═CH—CH₂,CH≡C—CH₂, CH₃—CH₂—OCO—CH₂, C₆H₄—CH₂ Ar₁=p, m-OCH₃; R₁═CH₃ and R₂═CH₃CH₂Ar₁=m, m′-OCH₃C₆H₄; R₁═CH₃ and R₂═CH₃CH₂ Ar₁=1,3-benzodioxol-5-yl;R₁=n-butyl; R₂═CH₃, CH₃—CH₂, CH₂═CH—CH₂, CH≡CH₂, C₆H₄—CH₂, pNO₂—C₆H₄—CH₂, CH₃CH₂OCO—CH₂ Ar₁=1,3-bromobenzodioxol-5-yl; R₁=n butyl;R₂═CH₃—CH₂ Ar₁=m, p OCH₃—C₆H₄; R₁=n butyl; R₂═CH₃CH₂Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃; R₂═O₆H₅ or p-OHC₆H₄ R═R₃HN andAr₁=1,3-benzodioxol-5-yl; R₁═CH₃; R₂═H, CH₃—(CH₂)₂, CH₃—(CH₂)₃, pCOOH—C₆H₄CH₂ Ar₁=1,3-benzodioxol-5-yl; R₁═CH₃—(CH₂)₃; R₂═CH₃—(CH₂)₂ orCH₃—(CH₂)₃ Ar₁=1,3-benzodioxol-5-yl; R₁═C₆H₅, R₂═CH₃—(CH₂)₂ Ar₁=p OH,m-OCH₃—C₆H₄ or m, p OH—C₆H₄; R₁═H; R₂═H.
 8. A pharmaceuticalcomposition, characterized in that it contains a therapeuticallyeffective amount of at least one derivative as claimed in claim
 1. 9.The pharmaceutical composition as claimed in claim 8, for the treatmentof neurodegenerative diseases, in particular Alzheimer's disease andother tau pathologies.
 10. The pharmaceutical composition as claimed inclaim 8, for the treatment of Pick's disease.
 11. The pharmaceuticalcomposition as claimed in claim 8, for the treatment of trisomy
 21. 12.A method of inhibiting DYRK1A comprising administering an imidazolonederivative of claim
 1. 13. A method for synthesizing the imidazolonederivatives of formula I as claimed in claim 1, characterized in that itcomprises the use of an arylidene thiohydantoin derivative correspondingto formula 3

in which: R₁, R₂ and Ar₁ are as defined in said claims.
 14. The methodas claimed in claim 13, characterized in that, in order to prepare theimidazolone derivatives in which R═R₂S, said method comprises reacting athiohydantoin derivative 3 with a halogenated derivative 3′ of formulaR₂X  (3′) with X═Cl, Br or I under conditions which make it possible toobtain an imidazolone derivative 4, of formula

in which: R₁, R₂ and Ar₁ are as defined above.
 15. The method as claimedin claim 12, characterized in that, in order to prepare the imidazolonederivatives of formula (I) in which R═R₂S with R₂ representing an arylgroup, said method comprises reacting the thiohydantoin derivative 3with an arylboronic acid 7′ of formulaAr₂B(OH)₂  (7′) under conditions which give the derivatives of formula 8


16. The method as claimed in claim 13, characterized in that, in orderto prepare the imidazolone derivatives in which R═R₃HN, said methodcomprises: either reacting an imidazolone derivative 4 with an amine 4′of formulaR₃—NH₂  (4′) under conditions which make it possible to obtain theimidazolone derivative 5 of formula

or reacting a hydantoin derivative 3 with an amine 4′.
 17. The method asclaimed in claim 13, characterized in that, in order to prepare theimidazolone derivatives of formula (I) in which R═R₄COHN, said methodcomprises reacting an imidazolone derivative 5 of formula

with an acid chloride 5′ of formulaR₄COCl  (5′) under conditions which make it possible to obtain animidazolone derivative 6 of formula


18. The method as claimed in claim 13, characterized in that, in orderto prepare the imidazolone derivatives in which R═Ar², said methodcomprises reacting a thiohydantoin derivative of formula 3 with anarylboronic acid 7′Ar₂B(OH)₂  (7′) under conditions which make it possible to obtain animidazolone derivative 7


19. The method as claimed in claim 13, characterized in that thethiohydantoin derivative 3 is obtained by reacting the derivative offormula 2

with an aldimine derivative of formula 2′Ar₁-CH═N-alk  (2′) the substituents being as defined above and “alk”representing a C₃-C₅ alkyl radical.
 20. The method as claimed in claim19, characterized in that the aldimine derivative 2′ is obtained byreacting an aldehyde 2″ Ar₁—CH═O and propylamine 2″ CH₃—(CH₂)₂—NH₂. 21.The method as claimed in claim 19, characterized in that thethiohydantoin derivative 2 is obtained by reacting methyl glycinatehydrochloride 1CH₃O₂C—CH₂—NH₂, HCl  (1) with an isothiocyanate 1′ of formulaR₁—N═C═S  (1′)